Superfund Research Program
Genomics and Analytical Chemistry
Over the past year, the Genomic and Analytical Chemistry Core has been developing and applying an innovative chemoproteomic strategy termed Isotopic Tandem Orthogonal Proteolysis-enabled Activity-based Protein Profiling (isoTOP-ABPP) to map proteome-wide targets of various environmental chemicals to better understand their toxicological mechanisms. IsoTOP-ABPP uses reactivity-based chemical probes to map proteome-wide reactive, functional, and ligandable hotspots directly in complex proteomes. When used in a competitive manner, small-molecules can be competed against binding of reactivity-based probes to ligandable hotspots to identify targets and off-targets of environmental chemicals. The Core has used isoTOP-ABPP to recently characterize the toxicological mechanisms of the widely used herbicides, acetochlor and glyphosate. They show that both chemicals, acetochlor in its parent form and glyphosate through its metabolism to glyoxylate, inhibit the catalytic cysteines of several thiolases involved in fatty acid oxidation in vivo in mouse liver. They show that inhibition of these targets leads to a diversion of fatty acids away from degradation and towards other lipid pathways, including triglycerides leading to hepatic steatosis. These studies have been accepted to American Chemical Society (ACS) Chemical Biology and Cell Chemical Biology, and will be published in the very near future.